Overexpression of liver-type phosphofructokinase (PFKL) in transgenic-PFKL mice: implication for gene dosage in trisomy 21.

The human liver-type subunit of the key glycolytic enzyme, phosphofructokinase (PFKL), is encoded by a gene residing on chromosome 21. This chromosome, when triplicated, causes the phenotypic expression of Down's syndrome (trisomy 21). Increased phosphofructokinase activity, a result of gene dosage, is commonly found in erythrocytes and fibroblasts from Down's syndrome patients. We describe the construction of transgenic mice overexpressing PFKL for use as a well-defined model system, in which the effects of PFKL overexpression in various tissues, and throughout development, can be studied. Mice transgenic for a murine PFKL 'gene cDNA' hybrid construct were found to overexpress PFKL in a tissue-specific manner resembling that of the endogenous enzyme. Although unchanged in adult brain, PFK specific activity was found to have been almost doubled in brains of embryonic transgenic-PFKL mice, suggesting that the extra copies of the PFKL gene are expressed during the developmental period. This pattern of overexpression of PFKL in brains of transgenic-PFKL mice suggests that gene-dosage effects may be temporally separated from some of their consequences, adding an additional layer of complexity to the analysis of gene dosage in trisomy 21.